Efficacy and tolerability of zonisamide as add-on in brain tumor-related epilepsy: preliminary report.

BACKGROUND: Zonisamide (ZNS) is an antiepileptic drug (AED) with broad spectrum action that demonstrated a good efficacy in controlling seizures as add-on in adult and pediatric epilepsy. To date there have been no studies on ZNS in patients with brain tumor-related epilepsy (BTRE). AIM OF THE STUDY: To evaluate efficacy and tolerability of ZNS as add-on in BTRE. METHODS: We followed six patients suffering from BTRE who had already been treated with other AEDs and who had had not experienced adequate seizure control. Three patients underwent chemotherapy while being treated with ZNS. Mean duration of follow-up was 8 months. RESULTS: Mean seizure number in the last month prior to the introduction of ZNS had been 27.7/month. ZNS mean dosage was of 283.3 mg/day. At last follow-up, the mean seizure number was reduced to 8.8/month. Responder rate was 83.3%.Two patients discontinued the drug because of side effects. There were no other reported side effects. CONCLUSIONS: Preliminary data on the use of ZNS in add-on in patients with BTRE indicate that this drug may represent a valid alternative as add-on in this particular patient population. However, larger samples are necessary to draw definitive conclusions.

Early post-operative MRI: correlation with progression-free survival and overall survival time in malignant gliomas.

Forty-seven patients with Glioblastoma (42) and Anaplastic Astrocytoma (5) were studied with MR 24 hrs after surgery. In order to evaluate the role of early MR in defining the extent of surgical resection and its relation with the prognosis of malignant glioma patients, three categories of surgical resection were considered: gross total, sub-total and partial resection. The results were correlated with progression-free survival (PFS) and overall survival (ST). As demonstrated by early-MR, gross total resection was performed in 17 patients, sub-total and partial resection in 19 and 11 patients, respectively. The PFS was 6 months in gross total resection, 6 and 3 months in sub-total and in partial resection, respectively. The median survival time was 16 months in total resection patients, 13 months and 7 months in sub-total resection and partial resection patients, respectively. The study confirms that early-MR has to be considered an accurate technique for monitoring the extension of malignant glioma surgical resection and shows a good correlation between early-MR findings, PFS and ST.

Defective human retinoblastoma protein identified by lack of interaction with the E1A oncoprotein.

Inactivating mutations of the retinoblastoma susceptibility gene (Rb) are involved in the pathogenesis of hereditary and sporadic retinoblastoma. Alterations in the Rb gene have also been found in several other human tumors occurring with epidemiological incidence higher than that of retinoblastoma. Four human malignant glioma cell lines were examined for abnormalities in the retinoblastoma gene product (pRb), using a procedure based on the interaction of pRb with an in vitro-translated adenovirus E1A oncoprotein. In the CRS-A2 cell line, derived from a glioblastoma multiforme, pRb did not bind with the in vitro-translated E1A protein. Restriction analysis of the CRS-A2 Rb gene and Rb mRNA expression provided patterns that could not be distinguished from the other glioma cell lines. Further investigation revealed the presence of a truncated pRb in the CRS-A2 cell line, due to a nucleotide insertion in the coding sequence at position 2550. In addition, this truncated Rb protein was undetectable in phosphorylated form. The binding assay with the in vitro-translated E1A was also used to study other cell lines with known mutations in the Rb gene. This method, which evaluates the interaction between in vitro-translated E1A and the pRb, is proposed as a rapid screening for detecting functional alterations in the retinoblastoma protein.

Calcified pituitary adenoma associated with severe hyperprolactinemia. Case report.

A patient with a completely calcified chromophobe adenoma is reported. Endocrine evaluation revealed very high prolactin levels. Such extensive calcifications in prolactin-secreting adenomas are extremely rare. The possible pathogenetic mechanisms of this association are discussed.

Differentiation of glioblastoma multiforme from astrocytomas by in vitro 1H MRS analysis of human brain tumors.

In vitro high resolution 1H NMR spectroscopy allows non-invasive metabolic evaluation of specimens derived from surgically biopsied or resected brain tumors, with the aim of identifying potential markers of different malignancy grading, and improving diagnostic and therapeutic strategies. In the present study we evaluated 36 patients affected by different brain gliomas (7 well differentiated astrocytomas, 7 anaplastic astrocytomas, 16 glioblastomas, 6 oligodendrogliomas). These analyses allowed discrimination between well differentiated and anaplastic astrocytomas (AII + AA) and glioblastoma multiforme (GM) samples on the basis of the ratio between the integrated choline-containing resonance (b"Cho") and the creatine peaks (creatine (Cr) + Phosphocreatine (PCr)). While no definite difference was found between AII and AA, significantly higher values were observed for this ratio in GM. Other signals, derived from different metabolites, such as Glycine (Gly) and N-acetyl-aspartate (NAA), may also assume relevance in differential tumor diagnosis. In this study an increased [Gly]/[Cr + PCr] ratio was observed in GM with respect to AII and AA. The NAA levels observed in our tumor specimens may be explained on the basis of tumor cell infiltration into brain adjacent tissue. Interesting, but inconclusive, are the data concerning oligodendrogliomas, which, also in well differentiated forms, exhibit increased levels of b"Cho"/(Cr + PCr) ratio. The present study confirms the role of MRS in the biochemical characterization of neoplastic brain tissue and its potential contribution to a better selection of multidisciplinary treatment strategies.

Comparative analysis of proliferating cell nuclear antigen and epidermal growth factor receptor expression in glial tumours: correlation with histological grading.

The present study analyzed the combined immunostaining for proliferating cell nuclear antigen (PCNA) and epidermal growth factor receptor (EGFR) with the aim of obtaining an objective method for the evaluation of the growth fraction in human glial tumors. A retrospective study was undertaken on 157 gliomas employing MoAb PC10 and MoAb 108, recognizing a 36 Kd nuclear protein associated with the cell cycle and the extracellular domain of the EGFR, respectively. The results of this immunohistochemical analysis showed that the rate of PCNA positive cell is directly associated to EGFR expression and significantly (P < 0.0001) correlates with tumor morphological grading, this was also the case in patients submitted to multiple surgical treatments for recurrent tumors. PCNA and/or EGFR are expressed by a minority of low grade astrocytoma, while anaplastic astrocytoma and glioblastoma displayed an intense immunoreactivity for the two antigens in more than 85% of tested cases. These findings indicate that the combined evaluation of PCNA and EGFR could allow a more definite biopathological grading of neuroepithelial brain tumours.

Incidence of phlogistic complications in infantile posterior fossa surgery according to the different preoperative diagnostic procedures.

Sixty seven infantile patients developing postoperative phlogistic complications as a consequence of posterior fossa surgery (i.e.: neoplasms, arachnoid cysts, A-V malformations) are herein studied. They have been subdivided in 2 groups in accordance to the different preoperative diagnostic procedures they underwent. In the first series 41 cases of posterior fossa anomalies have been diagnosed by means of air contrast ventriculography with or without cerebral angiography; in the other one the 26 patients were submitted to C.A.T. with or without angiography. In the first group the incidence rate of phlogistic complications was 31.7%, in the second one 3.8%. According to the authors this considerable difference is due to the diagnostic procedures employed. Contraindications to air contrast ventriculography and advantages of CT scan are widely discussed and emphasized.

Methodology of stereotactic biopsy.

The great technological improvement in the neurosurgical tools and in the neuroradiological imaging has brought about the diffusion of the stereotactic techniques. They are crucial for the diagnosis and treatment of intracranial expanding lesions of small dimensions or located in sites inaccessible to conventional techniques. The Authors describe the most common systems and methodologies for the stereotactic biopsy. They stress the importance of performing serial explorations which can provide evidence of the heterogeneity of the neoplastic lesion and of the infiltration of the brain adjacent to the tumor.

The progression in astrocytic tumors.

Progression represents the qualitative tumor evolution during the time. Recently it received great consideration, mainly since the introduction of the neuroradiological imaging (CT and MRI). A series of 224 supratentorial astrocytic tumors of the juvenile and adult age have been analyzed: we found the morphological features of progression in 26% of them. These data introduce, perhaps, the most important information about progression: the "crisis" of the concept that low-grade tumors are stable lesions during the time.

Surgical treatment of paediatric malignant neuroepithelial brain tumors.

The role of the neurosurgeon in dealing with malignant neuroepithelial brain tumors, both supra- and infratentorial, in paediatric age, is stressed; this because surgery is the main therapy, and also it is mandatory, in order to achieve the pathological diagnosis, essential for planning any kind of complementary treatment. Open surgery versus stereotactic biopsy is considered, with emphasis on brain stem tumors. The treatment of malignant tumor recurrencies is also discussed, and the indications of a second surgical look in patients harboring recurrent medulloblastoma is proposed for discussion, when long disease-free time occur and combined modality treatments are performed.

Human glioma lines as experimental model for biological and chemosensitivity studies.

The use of rodent tumor lines is no longer satisfactory for either biological and chemosensitivity studies because of their well demonstrated difference in behaviour when compared to human tumors. With the employment of human tumor cell lines, both in vitro and in vivo, in nude mice, it is now possible to utilize an extremely more reliable model system able to specifically evaluate many biological features of human tumors as well as their chemosensitivity. Particularly, glioma-derived human tumor lines which grow both in vitro and in nude mice, allowed to assess several parameters able to indicate new therapeutic strategies.

The membrane-bound hexokinase as a potential marker for malignancy in human gliomas.

Hexokinase is a key enzyme in carbohydrate metabolism. Its activity has been shown elevated in cells with high mitotic index. In particular, experimental cancer cells, due to their peculiar energy metabolism, display a hexokinase activity proportional to the degree of malignancy. This is the case also for human gliomas in which glucose metabolism, evaluated via positron emission tomography, has been shown to be predictive for patient prognosis. In order to better correlate these findings, specific reagents for tumor hexokinase (a polyclonal antibody and a full-length cDNA probe both specific for murine tumor hexokinase) have been successfully employed to quantitate the protein and its messenger in cultured cell lines; the antibody was also tested in four specimens obtained from human astrocytomas.

The role of immunocytochemical assays in the diagnosis of stereotactic biopsies from intracranial tumors.

A selected panel of monoclonal antibodies (MoAbs) directed to distinct tumor associated antigens (TAA) has been tested to define the capability of these reagents to differentiate among metastatic carcinoma, lymphoma and primary brain tumor on cytologic specimens obtained with stereotactic techniques. Results obtained on 50 patients bearing either single or multiple brain lesions demonstrated that immunocytochemical (ICC) methods can distinguish between primary brain tumor and brain metastasis suggesting, in 90% of patients with cryptic primary neoplasia, the site of origin of the tumor.

Lonidamine in the combined treatment of malignant gliomas. A randomized study.

Lonidamine (LND) is a drug that interferes with energy metabolism of cancer cells, principally inhibiting aerobic glycolytic activity, by its effect on mitochondrially-bound hexokinase (HK). In such way LND could impair energy-requiring processes, as recovery from potentially lethal damage, induced by radiation treatment and by some cytotoxic drugs. A randomized study started in November 1983, to evaluate the efficacy of LND in association with radiotherapy as first line treatment in malignant gliomas, after surgical procedure. LND was also used in association with Lomustine (CCNU) at the moment of documented clinical and neuroradiological recurrence. At the present time 60 patients entered the study, and 47 are evaluable. Present preliminary results are not statistically significant, however indicate that LND tends to prolong the median survival time and the rate of one year survivors.

Somatostatin receptor imaging in CNS tumours using 111In-octreotide.

This study evaluates the in vivo visualization of somatostatin (SS) receptors in central nervous system (CNS) tumours using 111In-octreotide imaging and discusses the clinical implications. Ninety-five patients with histologically confirmed diagnosis of CNS tumours were imaged 2-4 and 24 h after the intravenous injection of 111-185 MBq of 111In-octreotide. An uptake index was computed using tumour/non-tumour ratios evaluated using a standard region-of-interest method. Semi-quantitative immunohistochemical studies of SS binding sites were performed on frozen tumour sections. All meningiomas, most pituitary adenomas and many glial tumours showed a positive scan, whereas all neurinomas, craniopharingiomas and ependymomas had negative receptor scans. Radio-octreotide uptake varied among the SS receptor positive CNS tumours: very intense in meningioma, intermediate in pituitary adenoma and of a low grade in glioma. The results of immunohistochemical studies confirmed the scintigraphic findings in all cases. We believe 111In-octreotide is a suitable radiopharmaceutical for characterizing CNS tumours in vivo as SS receptor positive or negative. This new neuronuclear imaging technique may be useful for differential diagnosis in selected cases, for post-surgical follow-up and in the assessment of differentiation in glial tumours.

Epilepsy and gliomas: incidence and treatment in 119 patients.

One hundred and nineteen consecutive patients affected by supratentorial gliomas were studied in order to determine the incidence of seizure at diagnosis, the occurrence of subsequent seizures and the efficacy of anticonvulsant treatment. The overall incidence of seizures as presentation symptom was 52% (62 patients). Preoperative seizures were present in 83% of patients affected by low-grade astrocytoma, in 46% of patients affected by anaplastic astrocytoma and in 36% of patients affected by glioblastoma. Postoperative epilepsy refractory to anticonvulsant treatment significantly related to low-grade histology and presence of preoperative seizures occurred in 48% of patients. Adverse effects associated with anticonvulsants were observed in 33.8% of patients treated with phenobarbital, 14.3% in the group treated with carbamazepine and 12% of patients treated with vigabatrin. We conclude that anticonvulsant treatment in patients affected by gliomas is often ineffective and prophylactic treatment should be discontinued after 6 months in patients preoperative seizures free. In patients with high risk of seizures antiepileptic drugs with good efficacy and lower incidence of adverse effects than phenobarbital are indicated.

Potential role of in vitro 1H magnetic resonance spectroscopy in the definition of malignancy grading of human neuroepithelial brain tumours.

The increasing sensitivity of neuro-imaging in the diagnosis of brain expanding lesions is not directly related to biopathological specificity and new technological approaches are under study. In particular Magnetic Resonance Spectroscopy (MRS) allows evaluation of some biochemical pathways whose metabolic alterations may be correlated with the nature and malignancy grading of primary brain tumours. In the present study the author performed an in vitro high field 1H MRS (9.4 and 14.1 T) analysis of specimens obtained from stereotactic biopsy or microsurgical removal of primary brain tumours. Different samples derived from heterogeneous areas and/or infiltrated perilesional regions were examined. This study was principally focused on malignancy grading of gliomas and its correlation with the ratio (R) between the resonance band arising from choline containing compounds (between 3.14 and 3.35 ppm) and the total creatine signal (3.0 ppm). Analyses allowed significant discrimination between astrocytomas (R = 2.4 +/- 0.6) and glioblastoma (GBM) (R = 4.4 +/- 1.3) [p < 0.002]; however the results did not allow discrimination between differentiated and anaplastic astrocytomas. The GBM showed the largest spread of values corresponding to their higher level of tissue heterogeneity and de-differentiation. Studies on non astrocytic brain tumours indicated that even higher R values were exhibited by oligodendrogliomas, even in well differentiated forms (p < 0.02 with respect to GBM). Moreover, preliminary observations indicated that signals arising from other metabolites may also contribute to a differential diagnosis of different oncotypes. Among these glycine appears particularly relevant, since higher levels were measured for this amino acid in GBM with respect to both astrocytomas and oligodendrogliomas.

[Primary empty sella. Clinico-radiologic considerations in 18 cases]. / La sella vuota primaria. Considerazioni clinico-radiologiche a proposito di 18 casi.

18 patients with "primary empty sella" were reviewed for this study. In 3 of them the sellar enlargement was discovered occasionally by performing skull radiographs for other reasons. The galattorrhea-dismenorrhea or amenorrhea syndrome and obesity were the most common clinical features. Endocrinological tests were normal in ten patients and abnormal in eight. Slight elevation of serum PRL was the most common record. 12 patients had enlarging of the sella turcica; in 4, only the floor was asymmetric and in 2 the sella was quite normal. In 5 patients C.T. without intra-thecal contrast was sufficient to discover the E.S. In 13 patients we performed C.T. cysternography by injecting in the lumbar subarachnoid space 8-10 ml of Iopamidolo 200. This is an excellent and safe technique to perform C.T. cysternography.

The VEP in evaluation of pituitary tumors.

12 patients with pituitary tumors were studied with VEP, to demonstrate involvement of the optic chiasma. In 3 patients VEP was recorded pre- and post-surgery to evaluate a modification in the shape and latencies of the potentials. 2 patients were studied only pre-surgery, the other 7 post-surgery. The utility of this test is discussed.

Brain-stem auditory evoked potentials in supratentorial brain tumors.

A group of 42 adult patients with supratentorial brain tumors were studied with computed tomography (CT or/and NMR) and brain-stem evoked potentials (BAEPs). 12 patients had meningiomas and 30 had malignant tumors (gliomas and metastases). The latencies of wave V and of the interpeak latency I-III, III-V and I-V were evaluated both on the lesion side and the opposite side. In meningiomas mean latencies did not show significant differences from normal, while mean latencies in malignant tumors were significantly prolonged, except for the I-III interpeak latency. The results of this study demonstrate that BAEPs may be altered by supratentorial brain tumors. This examination appears to be useful in the monitoring of these lesions after treatment.